Lectured by

Md Abdul Barek
Lecturer
Department of Pharmacy
Noakhali science and Technology University
 Drug
Interaction
- Drug Interaction (DI) refers to the interaction
between two or more drugs administered
simultaneously result in an alteration of
pharmacological response of active drugs.

- Drug interactions may simply be thought of as

the actions of one drug being enhanced or
inhibited by the presence or actions of another
drug or exogenous substance.

- These may be adverse or beneficial.

- Multiple drug therapy
- Multiple prescriber
- Multiple pharmacological effects of drug
- Multiple disease condition
- Poor patient compliance
- Age of patient
- Drug related factors
 Precaution for Drug Choice

- When considering drug interactions the following, in

particular, may alert the practitioner to potential
problems, which may predispose towards an
interaction:
• Drugs with a narrow therapeutic window:
anti- coagulants, anticonvulsants, digoxin,
lithium, theophylline and cytotoxic agents
• Metabolic enzyme inducers and inhibitors
• Drugs with similar pharmacological effects
Continue…
 Mechanism of Drug Interaction

- Pharmacokinetic Interaction
- Pharmacodynamic Interaction
- Pharmaceutical Interaction
- Food-drug Interaction
- Plant herb-drug Interaction
- Drug alcohol interactions
- Drug tobacco interactions
 Pharmacokinetic Interaction

- Absorption
- Drug Distribution
- Drug Metabolism
- Elimination Interactions
 Absorption

Following oral administration, drugs are absorbed through the

mucous membranes of the gastro-intestinal tract. A number of
factors can affect the rate of absorption or the extent of
absorption (i.e. the total amount of drug absorbed).
1. Changes in gastro-intestinal pH
2. Adsorption, chelation and other complexing
mechanisms
3. Effects on gastro-intestinal motility.
4. Induction or inhibition of drug transport
proteins.
5. Malabsorption.
 01. Changes in gastro-intestinal pH

- The absorption of a drug across mucous membranes

depends on the extent to which it exists in the non-
ionised, lipid-soluble form.
- The ionisation state depends on the pH of its milieu,
the pKa of the drug and formulation factors.
- Weakly acidic drugs, such as the salicylates, are
better absorbed at low pH because the non-ionised
form predominates.
- An alteration in gastric pH due to antacids, histamine
H2 antagonists or proton pump inhibitors therefore
has the potential to affect the absorption of other
drugs.
 01. Changes in gastro-intestinal pH
- The clinical significance of antacid-induced changes in
gastric pH is not certain, particularly since relatively
little drug absorption occurs in the stomach. Changes
in gastric pH tend to affect the rate of absorption rather
than the extent of absorption, provided that the drug is
acid labile.
- Antacids, histamine H2 antagonists and omeprazole
can significantly decrease the bioavailability of
ketoconazole and itraconazole, which require gastric
acidity for optimal absorption, but the absorption of
fluconazole and voriconazole is not significantly
altered by changes in gastric pH.
02. Adsorption, chelation and other complexing mechanisms

- Certain drugs react directly within the gastro-intestinal

tract to form chelates and complexes which are not
absorbed.
- The drugs most commonly implicated in this type of
interaction include tetracyclines and the quinolone
antibiotics that can complex with iron, and antacids
containing calcium, magnesium and aluminium.
Tetracyclines can chelate with divalent or trivalent
metal cations such as calcium, aluminium, bismuth
and iron to form insoluble complexes, resulting in
greatly reduced plasma tetracycline concentrations.
02. Adsorption, chelation and other complexing mechanisms

- The absorption of propranolol, digoxin, warfarin,

tricyclic antidepressants, ciclosporin and
levothyroxine is reduced by colestyramine.
- Most chelation and adsorption interactions can be
avoided if an interval of 2–3 h is allowed between
doses of the interacting drugs.
 03. Effects on gastro-intestinal motility
- Since most drugs are largely absorbed in the upper part of the
small intestine, drugs that alter the rate at which the stomach
empties its contents can affect absorption.
- Drugs with anticholinergic effects, such as tricyclic
antidepressants, phenothiazines and some antihistamines, decrease
gut motility and delay gastric emptying.
- The outcome of the reduced gut motility can either be an increase
or a decrease in drugs given concomitantly. For example, tricyclic
antidepressants can increase dicoumarol absorption, probably as a
result of increasing the time available for its dissolution and
absorption. Opioids such as diamorphine and pethidine strongly
inhibit gastric emptying and greatly reduce the absorption rate of
paracetamol, without affecting the extent of absorption.
03. Effects on gastro-intestinal motility
- Codeine, however, has no significant effect on
paracetamol absorption. Metoclopramide increases
gastric emptying and increases the absorption rate of
paracetamol, an effect which is used to therapeutic
advantage in the treatment of migraine to ensure rapid
analgesic effect. It also accelerates the absorption of
propranolol, mefloquine, lithium and ciclosporin. This
type of interaction is rarely clinically significant.
04. Induction or inhibition of drug transport proteins
- The oral bioavailability of some drugs is limited by the
action of drug transporter proteins, which eject drugs
that have diffused across the gut lining back into the
gut.
- Digoxin is a substrate of P-glycoprotein and drugs that
inhibit P-glycoprotein, such as verapamil, may
increase digoxin bioavailability with the potential for
digoxin toxicity
 05. Malabsorption
- Drugs such as neomycin may cause a malabsorption
syndrome leading to reduced absorption of drugs such as
digoxin.
- Orlistat is a specific long-acting inhibitor of gastric and
pancreatic lipases, thereby preventing the hydrolysis of
dietary fat to free fatty acids and triglycerides.
- This can theoretically lead to reduced absorption of fat-
soluble drugs co-administered with orlistat. There has been
recent concern about potential decreased absorption of
levothyroxine and anti-epileptic drugs such as valproate
sodium and lamotrigine.
 Drug Distribution
- Following absorption, a drug undergoes distribution to various
tissues including to its site of action. Many drugs and their
metabolites are highly bound to plasma proteins.
- Albumin is the main plasma protein to which acidic drugs such as
warfarin are bound, while basic drugs such as tricyclic
antidepressants, lidocaine, disopyramide and propranolol are
generally bound to α1-acid glycoprotein.
- During the process of distribution, drug interactions may occur,
principally as a result of displacement from protein-binding sites.
- For example, if a patient taking phenytoin is given a drug which
displaces phenytoin from its binding sites, the total (i.e. free plus
bound) plasma phenytoin concentration will fall even though the
free (active) concentration remains the same.
- Lidocaine has been given as an example of a drug fitting these
criteria.
 Drug Metabolism
- Most clinically important interactions involve the effect of one
drug on the metabolism of another. Metabolism refers to the
process by which drugs and other compounds are biochemically
modified to facilitate their degradation and subsequent removal
from the body. The liver is the principal site of drug metabolism,
although other organs such as the gut, kidneys, lung, skin and
placenta are involved.
- Drug metabolism consists of phase I reactions such as oxidation,
hydrolysis and reduction, and phase II reactions, which primarily
involve conjugation of the drug with substances such as glucuronic
acid and sulphuric acid. Phase I metabolism generally involves the
cytochrome P450 (CYP450) mixed function oxidase system. The
liver is the major site of cytochrome 450-mediated metabolism, but
the enterocytes in the small intestinal epithelium are also
potentially important.
 Drug Metabolism
CYP450 isoenzymes
- The CYP450 system comprises 57 isoenzymes, each derived from
the expression of an individual gene.
- CYP3A is probably the most important of all drug-metabolising
enzymes because it is abundant in both the intestinal epithelium
and the liver and it has the ability to metabolise a multitude of
chemically unrelated drugs from almost every drug class.
- The effect of a cytochrome 450 isoenzyme on a particular substrate
can be altered by interaction with other drugs.
- Drugs may be themselves substrates for a cytochrome 450
isoenzyme and/or may inhibit or induce the isoenzyme.
- Erythromycin (an inhibitor of CYP3A4) is taken by a patient being
given carbamazepine (which is extensively metabolised by
CYP3A4), this may lead to toxicity due to higher concentrations of
- carbamazepine.
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Enzyme Induction
- The most powerful enzyme inducers in clinical use are the
antibiotic rifampicin and antiepileptic agents such as
- barbiturates, phenytoin and carbamazepine. Some enzyme
inducers, notably barbiturates and carbamazepine, can
induce their own metabolism (autoinduction).
- Cigarette smoking, chronic alcohol use and the herbal
preparation St John's wort can also induce drug-
metabolising enzymes.
- Enzyme induction usually results in a decreased
pharmacological effect of the affected drug.
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Enzyme Inhibition
- Many drugs act as inhibitors of cytochrome 450 enzymes.
- The clinical significance of this type of interaction depends
on various factors, including dosage (of both drugs),
alterations in pharmacokinetic properties of the affected
drug such as half-life and patient characteristics such as
disease state. Interactions of this type are again most likely
to affect drugs with a narrow therapeutic range such as
theophylline, ciclosporin, oral anticoagulants and
phenytoin. For example, starting treatment with an enzyme
inhibitor such as ritonavir in a patient taking sildenafil
could result in a marked increase in sildenafil plasma
concentrations.
 Elimination Interactions
- Changes in urinary pH
- Changes in active renal tubule excretion
- Changes in renal blood flow
- Biliary excretion and the enterohepatic shunt
- Drug transporter proteins
 Changes in urinary pH
- As with drug absorption in the gut, passive reabsorption of drugs
depends on the extent to which the drug exists in the non-ionised
lipid-soluble form.
- Only the non-ionised form is lipid soluble and able to diffuse back
through the tubular cell membrane.
- Thus, at alkaline pH, weakly acidic drugs (pKa 3.0–7.5) largely
exist as ionised lipid-insoluble molecules which are unable to
diffuse into the tubule cells and will therefore be lost in the urine.
- Conversely, the clearance of weak bases (pKa 7.5–10) is higher in
acid urine.
- Furthermore, drugs that produce large changes in urine pH are
rarely used clinically. Urine alkalinisation or acidification has been
used as a means of increasing drug elimination in poisoning with
salicylates and amphetamines, respectively.
Changes in active renal tubule excretion
- Drugs that use the same active transport system in the kidney
tubules can compete with one another for excretion.
- For example, probenecid may be given to increase the plasma
concentration of penicillins by delaying renal excretion.
- Increased methotrexate toxicity, sometimes life- threatening, has
been seen in some patients concurrently treated with salicylates
and some other non-steroidal anti-inflammatory drugs (NSAIDs).
The development of toxicity is more likely in patients.
 Changes in renal blood flow
- Blood flow through the kidney is partially controlled by the
production of renal vasodilatory prostaglandins. If the synthesis of
these prostaglandins is inhibited by drugs such as indometacin, the
renal excretion of lithium is reduced with a subsequent rise in
plasma levels.
- The mechanism underlying this interaction is not entirely clear, as
plasma lithium levels are unaffected by other potent prostaglandin
synthetase inhibitors, for example, aspirin. If an NSAID is
prescribed for a patient taking lithium, the plasma levels should be
closely monitored.
Biliary excretion and the enterohepatic shunt
- Number of drugs are excreted in the bile, either unchanged or
conjugated, for example, as the glucuronide, to make them more
water soluble.
- Antibiotics may reduce the enterohepatic circulation of
ethinyloestradiol conjugates, leading to reduced circulating
oestrogen levels with the potential for therapeutic failure.
 Drug transporter proteins
- Drugs and endogenous substances are now known to cross
biological membranes not just by passive diffusion but by carrier-
mediated processes, often known as transporters.
- P-glycoprotein (P-gp) is a large cell membrane protein that is
responsible for the transport of many substrates, including drugs.
- P-glycoprotein acts as an efflux pump, exporting substances into
urine, bile and the intestinal lumen. Its activity in the blood–brain
barrier limits drug accumulation in the central nervous system
(CNS).
- Many drugs that are substrates for CYP3A4 are also substrates for
P-glycoprotein.
 Pharmacodynamic interactions
- Pharmacodynamic interactions are those where the effects of one
drug are changed by the presence of another drug at its site of
action.
- Sometimes these interactions involve competition for specific
receptor sites but often they are indirect and involve interference
with physiological systems.
- They are much less easy to classify than interactions with a
pharmacokinetic basis.
1. Antagonistic interactions
2. Additive or synergistic interactions
3. Drug or neurotransmitter uptake
interactions
4. Receptor Interaction
 Antagonistic interactions
- It is to be expected that a drug with an agonist action at a particular
receptor type will interact with antagonists at that receptor.
- For example, the bronchodilator action of a selective β2-
adrenoreceptor agonist such as salbutamol will be antagonised by
β-adrenoreceptor antagonists.
- There are numerous examples of interactions occurring at receptor
sites, many of which are used to therapeutic advantage.
- Specific antagonists may be used to reverse the effect of another
drug at receptor sites; examples include the opioid antagonist
naloxone and the benzodiazepine antagonist flumazenil. α-
Adrenergic agonists such as metaraminol may be used in the
management of priapism induced by α-adrenergic antagonists
such as phentolamine.
 Additive or synergistic interactions
- If two drugs with similar pharmacological effects are given
together, the effects can be additive
- Although not strictly drug interactions, the mechanism frequently
contributes to ADR.
- For example, the concurrent use of drugs with CNS depressant
effects such as antidepressants, hypnotics, antiepileptics and
antihistamines may lead to excessive drowsiness, yet such
combinations are frequently encountered.
- Combinations of drugs with arrhythmogenic potential such as
antiarrhythmics, neuroleptics, tricyclic antidepressants and
those producing electrolyte imbalance (e.g. diuretics) may lead
to ventricular arrhythmias and should be avoided.
Drug or neurotransmitter uptake interactions
- Although seldom prescribed nowadays, the MAOIs have
significant potential for interactions with other drugs and foods.
- MAOIs reduce the breakdown of noradrenaline in the adrenergic
nerve ending. Large stores of noradrenaline can then be released
into the synaptic cleft in response to either a neuronal discharge or
an indirectly acting amine.
- The action of the directly acting amines adrenaline, isoprenaline
and noradrenaline appears to be only moderately increased in
patients taking MAOIs.
- In contrast, the concurrent use of MAOIs and indirectly acting
sympathomimetic amines such as amphetamines, tyramine,
MDMA (ecstasy), phenylpropanolamine and pseudoephedrine
can result in a potentially fatal hypertensive crisis.
Drug or neurotransmitter uptake interactions
- The risk of interactions continues for several weeks after the
MAOI is stopped as new monoamine oxidase enzyme must be
synthesised. Patients taking irreversible MAOIs should not take
any indirectly acting sympathomimetic amines. All patients must
be strongly
 Receptor Interaction
1. Homodynamic
- Binding to the same receptor site
- Antagonism of opioids and naloxone (antidote)
- Both compete for the same receptor site; mu-opioid receptor
(MOR), a G protein-coupled receptor, present at CNS.
- Antagonism of ibuprofen and aspirin Both compete for the
same receptor site of cyclooxygenase.
 Receptor Interaction
2. Allosteric modulation
- binding to the same receptor, but at different sites
- Agonist effect of barbiturates (which are GABA receptor agonists)
and benzodiazepines (which are positive allosteric modulators of
the same receptor)
 Receptor Interaction
3. Heterodynamic
- Binding to different receptors, but affecting the same second
messenger system.
- Antagonist effect of glucagon upon the cyclic AMP second
messenger effects of β2-blockers.
- Beta 2 blocker inhibits relaxation of smooth muscle in blood
vessels, bronchi, the gastrointestinal system, and the genitourinary
tract. In addition, it also inhibits both glycogenolysis and
gluconeogenesis, which may result in hypoglycemia.
 Receptor Interaction
4. Second messenger effects
- Binding to different receptor/messenger systems, but having effect
on the same physiological process
- The synergistic effect of sedative agents upon the decrease in the
level of consciousness.
- Eg: the combination of benzodiazepines and propofol, because of
its rapid induction and recovery time
 Drug–food interactions
- It is well established that food can cause clinically important
changes in drug absorption through effects on gastro-intestinal
absorption or motility, hence the advice that certain drugs should
not be taken with food, for example, iron tablets and antibiotics.
- Two other common examples already outlined include the
interaction between tyramine in some foods and MAOIs, and
the interaction between grapefruit juice and the calcium
channel blocker felodipine.
- With improved understanding of drug metabolism mechanisms,
there is greater recognition of the effects of some foods on drug
metabolism. The interaction between grapefruit juice and
felodipine was discovered serendipitously when grapefruit juice
was chosen to mask the taste of ethanol in a study of the effect of
ethanol on felodipine.
 Drug–food interactions
- Initial reports of an interaction between cranberry juice and
warfarin, prompting regulatory advice that the international
normalised ratio (INR) should be closely monitored in patients
taking this combination, have not been confirmed by subsequent
controlled studies.
- Cruciferous vegetables, such as brussels sprouts, cabbage and
broccoli, contain substances that are inducers of the CYP450
isoenzyme CYP1A2. Chemicals formed by burning (e.g.
barbecuing) meats additionally have these properties.
- These foods do not appear to cause any clinically important drug
interactions in their own right, but their consumption may add
another variable to drug interaction studies, so complicating
interpretation.
 Drug–food interactions
Warfarin and Vitamin K:
- Warfarin (Coumadin) is a blood-thinning medication that helps
treat and prevent blood clots. Eating certain foods, especially those
rich in vitamin K, can diminish warfarin’s effectiveness.
- The highest concentrations of vitamin K are found in green leafy
vegetables such as spinach, Brussels sprouts, broccoli, asparagus.
 Drug–food interactions
Insulin, Oral Diabetic Agents, and Alcohol:
- An alcoholic drink can increase or prolong the effects of insulin or
oral diabetic agents (pills) and thus lead to hypoglycemia or low
blood sugar.
- The glucose-lowering action of alcohol can last as long as 08 to 12
hours.
 Drug–food interactions
Statins and Grapefruit:
- Statins are highly effective cholesterol-lowering drugs. Drinking
grapefruit juice or eating fresh grapefruit can increase the amount
of some statins in blood and lead to potentially greater side effects
of these drugs.
- Side effects of statins include muscle soreness and liver
abnormalities reflected in high transaminase levels on a blood test.
- This interaction is especially strong with simvastatin and
lovastatin, milder with atorvastatin.
- So, it’s important for elders to check whether their prescribed
statin drugs do interact before giving up vitamin C-rich grapefruit.
 Drug–food interactions
Calcium Channel Blockers and Grapefruit:
- Calcium channel blockers are prescribed for high blood pressure.
A natural element found in grapefruit latches onto the intestinal
enzyme called CYP3A4, which alters the breakdown of the
calcium channel blockers, possibly resulting in excessively high
blood levels of the drug, along with an increased risk of serious
side effects.
 Drug–food interactions
Antibiotics and Dairy Products:
- Dairy products such as milk, yogurt, and cheese can delay or
prevent the absorption of antibiotics such as tetracyclines and
ciprofloxacin.
- This occurs because the calcium in such foods binds to the
antibiotics in the stomach and upper small intestine to form an
insoluble compound.
- To avoid problems, taking an antibiotic one hour before or two
hours after a meal is recommended.
- However, there’s no need to avoid milk and dairy with all
antibiotics. For example, it’s recommended that metronidazole
should be taken with water or milk to prevent stomach upset.